Peanut allergy is one of the most serious of the immediate hypersensitivity reactions to foods in terms of persistence and reaction severity and appears to be a growing problem without effective treatment. The goal of this proposal is to develop allergen IT for patients with peanut allergic reactions. Based on a novel idea that allergen-specific, sublingual immunotherapy (SLIT) would desensitize or tolerize allergic patients, we propose to utilize this alternative therapy in peanut-allergic patients. Previous trials of peanut-specific immunotherapy have not utilized the sublingual route for treatment. By specifically targeting patients who are at risk for life-long peanut sensitivity (peanut specific IgE > 15 klU/ml and significant initial symptoms) we anticipate being able to desensitize or induce clinical tolerance in these patients to cause long term immune modulation of their allergic response. Our hypothesis is that peanut SLIT will desensitize patients with peanut allergic reactions by the induction of peanut specific regulatory T cells resulting in immune modulation of the peanut allergic reaction. Effective peanut SLIT desensitization would benefit patients by causing them to eventually lose their clinical sensitivity to peanut and by assuring that they will not have life-threatening allergic reactions to contaminating amounts of peanuts. We will determine if peanut SLIT can alter the natural history of peanut allergy in peanut allergic patients. We also we anticipate they will exhibit a greater decrease in wheal size from a peanut prick skin test and a greater decrease in serum specific IgE to peanut. We will determine if peanut SLIT reduces the number and/or symptoms of accidental peanut ingestion. We expect the immunologic effect of peanut SLIT would be either 1) the induction of regulatory T cells, or 2) a conversion from a cellular Th2 to Th1 response. Understanding the cellular dynamics following peanut SLIT will allow us to determine if this is an appropriate initial step in the eventual development of a safe and efficacious treatment for peanut-allergy. An understanding of the molecular mechanisms of peanut allergy is vital to ensure the successful treatment of peanut-allergic patients. There is a lack of acceptance of SLIT by traditionally trained allergists/immunology specialists. The proposed collaboration of two groups, Allergy Associates of La Crosse, Wisconsin and Duke Univ., brings together extensive clinical and research experience to successfully conduct this feasibility trial. The significance of this proposal is that if peanut SLIT in peanut allergic patients is effective, the treatment would provide an immediate therapeutic option for patients.